A new and promising approach to the treatment of oral cancer is by viruses that replicate in the tumor, thus eliminating the malignant cells. A virus that could be used for this purpose is the Herpes simplex virus type-1 (HSV-1), but it will be useful only if its potency can be increased and its safety can be improved. To increase the potency of the virus we will find how it can be combined with the use of irradiation or anti-cancer drugs in such a way as to increase its replication. The role of the cell cycle in making tumors more susceptible to the virus will be determined. To improve the safety of the virus we will find the effects of replacing the promoter of an essential gene of the virus with a fragment of the human papillomavirus, which is very specific for cancer cells. The hypothesis to be tested is that the papillomavirus promoter will allow HSV-1 to retain its toxicity for oral cancer cells while making it less toxic to cells derived from other tissues. The appropriate combination of conventional anti-cancer agents with a virus that has been modified to increase its anti-cancer specificity will produce improved opportunities for the treatment of oral cancer. This project is directed toward improved methods of treating cancer. We have modified a human virus with the goal of using it to infect cancers and eliminate them. We will find ways to make the virus more potent, but at the same time more safe.